The present invention relates to novel carboxylic acid derivatives, their preparation and use.
Endothelin is a peptide which consists of 21 amino acids and is synthesized and released by vascular endothelium. Endothelin exists in three isoforms, ET-1, ET-2 and ET-3. xe2x80x9cEndothelinxe2x80x9d or xe2x80x9cETxe2x80x9d hereinafter means one or all isoforms of endothelin. Endothelin is a potent vasoconstrictor and has a great effect on vessel tone. It is known that this vasoconstriction is caused by binding of endothelin to its receptor (Nature, 332, 1988, 411-415; FEBS Letters, 231, 1988, 440-444 and Biochem. Biophys. Res. Commun., 154, 1988, 868-875).
Increased or abnormal release of endothelin causes persistent vasoconstriction in peripheral, renal and cerebral vessels, which may lead to disorders. As reported in the literature, endothelin is involved in a number of disorders. These include: hypertension, acute myocardial infarct, pulmonary hypertension, Raynaud""s syndrome, cerebral vasospasms, stroke, benign prostate hypertrophy, atherosclerosis and asthma (J. Vascular Med. Biology 2, (1990) 207, J. Am. Med. Association 264, (1990) 2868, Nature 344, (1990) 114, N. Engl. J. Med. 322, (1989) 205, N. Engl. J. Med. 328, (1993) 1732, Nephron 66, (1994) 373, Stroke 25, (1994) 904, Nature 365, (1993) 759, J. Mol. Cell. Cardiol. 27, (1995) A234; Cancer Research 56, (1996) 663).
At least two endothelin receptor subtypes, ETA and ETB receptors, have been described in the literature (Nature 348, (1990) 730, Nature 348, (1990) 732). Accordingly, substances which inhibit the binding of endothelin to the two receptors ought to antagonize the physiological effects of endothelin and therefore be valuable drugs.
WO 96/11914 describes carboxylic acid derivatives which, however, bind with high affinity to the ETA receptor and with considerably less affinity to the ETB receptor (called ETA-specific antagonists).
ETA-specific antagonists mean here those antagonists whose affinity for the ETA receptor is at least twenty times higher than their affinity for the ETB receptor.
It is an object of the present invention to provide endothelin receptor antagonists which bind with approximately the same affinity to the ETA and ETB receptors (called mixed antagonists).
Approximately the same affinity for the receptors means that the ETA:ETB affinity ratio is greater than 0.1 and less than 20, preferably less than 10.
We have found that this object is achieved by carboxylic acid derivatives of the formula I 
where R1 is tetrazole [sic] or a group 
where R has the following meaning:
a) a radical OR7 where R7 is:
hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal, a physiologically tolerated organic ammonium ion such as C1-C4-alkylammonium or the ammonium ion;
C3-C8-cycloalkyl, C1-C8-alkyl, CH2-phenyl which can be substituted by one or more of the following radicals: halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, hydroxyl, C1-C4-alkoxy, mercapto, C1-C4-alkylthio, amino, carboxyl, NH(C1-C4-alkyl), N(C1-C4-alkyl)2;
C3-C6-alkenyl or C3-C6-alkynyl, it being possible for these groups in turn to carry one to five halogen atoms;
R7 can furthermore be a phenyl radical which may carry one to five halogen atoms and/or one to three of the following radicals, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, hydroxyl, C1-C4-alkoxy, mercapto, C1-C4-alkylthio, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2;
b) a 5-membered heteroaromatic system which is linked via a nitrogen atom, such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which may carry one to two halogen atoms or one to two C1-C4-alkyl or one to two C1-C4-alkoxy groups;
c) a group 
xe2x80x83where k is 0, 1 and 2, p is 1, 2, 3 and 4 and R8 is
C1-C4-alkyl, C3-C8-cycloalkyl, C3-C6-alkenyl, C3-C6-alkynyl or phenyl which can be substituted by one or more, eg. one to three, of the following radicals: halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, hydroxyl, C1-C4-alkoxy, C1-C4-alkylthio, mercapto, amino, carboxyl, NH(C1-C4-alkyl), N(C1-C4-alkyl)2;
d) a radical 
xe2x80x83in which R9 is:
C1-C4-alkyl, C3-C6-alkenyl, C3-C6-alkynyl, C3-C8-cycloalkyl, C1-C4-haloalkyl, it being possible for these radicals to carry a C1-C4-alkoxy, C1-C4-alkylthio and/or a phenyl radical as mentioned under c);
phenyl, unsubstituted or substituted, in particular as mentioned above,
e) R1 can furthermore be 
xe2x80x83where R13 and R14 can be identical or different and have the following meanings:
hydrogen, C1-C8-alkyl, C3-C8-cycloalkyl, C3-C8-alkenyl, C3-C8-alkynyl, benzyl, phenyl which may carry one to five halogen atoms and/or one to three of the following radicals: nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, hydroxyl, C1-C4-alkoxy, mercapto, C1-C4-alkylthio, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2,
or R13 and R14 together form a C4-C7-alkylene chain which is closed to form a ring and which may be substituted by C1-C4-alkyl and in which an alkylene group may be replaced by oxygen, sulfur or nitrogen, such as xe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)5xe2x80x94, xe2x80x94(CH2)6xe2x80x94, xe2x80x94(CH2)2xe2x80x94Oxe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)7xe2x80x94, xe2x80x94CH2xe2x80x94Sxe2x80x94(CH2)2xe2x80x94, xe2x80x94CH2xe2x80x94NHxe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)2xe2x80x94Nxe2x80x94(CH2)2xe2x80x94;
R2 hydrogen, hydroxyl, NH2, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, halogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-hydroxyalkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkylthio, or CR2 is linked to CR10 as indicated below to give a 5- or 6-membered ring.
X nitrogen or methine.
Y nitrogen or methine.
Z nitrogen or CR10, where R10 is hydrogen or C1-C4-alkyl, or CR10 forms together with CR2 or CR3 a 5- or 6-membered alkylene or alkenylene ring which may be substituted by one or two C1-C4-alkyl groups and in which in each case one or more methylene groups can be replaced by oxygen, sulfur, xe2x80x94NH or N(C1-C4-alkyl)2.
At least one of the ring members X, Y or Z is nitrogen.
R3 hydrogen, hydroxyl, NH2, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, halogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-hydroxyalkyl or C1-C4-alkylthio, or CR3 is linked to CR10 as indicated above to give a 5- or 6-membered ring.
R4 and R5 (which may be identical or different):
phenyl or naphthyl, which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, mercapto, C1-C4-alkyl, C2-C4-alkenyl, C1-C4-hydroxyalkyl, C2-C4-alkynyl, C1-C4-haloalkyl, C1-C4-alkoxy, phenoxy, carboxyl, C1-C4-haloalkoxy, C1-C4-alkylthio, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2 or phenyl which can be substituted one or more times, eg. one to three times by halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkylthio; or phenyl or naphthyl, which are linked together in the ortho positions by a direct linkage, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO2, NH or N-alkyl group;
C3-C8-cycloalkyl.
R6 C3-C8-Cycloalkyl, it being possible for these radicals in each case to be substituted one or more times by: halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C1-C4-alkoxy, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3-C6-alkenyloxy, C3-C6-alkynyloxy, C1-C4-alkylthio, C1-C4-haloalkoxy, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, C3-C8-alkyl-carbonylalkyl, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, or phenyl which can be substituted one or more times, eg. one to three times, by halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkylthio;
phenyl or naphthyl, each of which can be substituted by one or more of the following radicals: halogen, R15, nitro, mercapto, carboxyl, cyano, hydroxyl, amino, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3-C6-alkenyloxy, C1-C4-haloalkyl, C3-C6-alkynyloxy, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-alkoxy, C1-C4-haloalkoxy, phenoxy, C1-C4-alkylthio, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, dioxomethylene [sic], dioxoethylene [sic] or phenyl which can be substituted one or more times, eg. one to three times, by halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkylthio;
a five- or six-membered heteroaromatic system containing one to three nitrogen atoms and/or one sulfur or oxygen atom, which may carry one to four halogen atoms and/or one to two of the following radicals: C1-C4-alkyl, C2-C4-alkenyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-alkylthio, phenyl or phenoxy it being possible for the phenyl radicals in turn to carry one to five halogen atoms and/or one to three of the following radicals: C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and/or C1-C4-alkylthio;
R15 is C1-C4-alkyl, C1-C4-alkylthio or C1-C4-alkoxy which carry one of the following radicals: hydroxyl, carboxyl, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, carboxamide [sic] or CON(C1-C4-alkyl)2;
W sulfur or oxygen.
Q a spacer whose length corresponds to that of a C2-C4 chain. The function of Q is to produce a defined distance between the groups R6 and W in the compounds of the formula I. The distance should correspond to the length of a C2-C4-alkyl chain. This can be achieved by a large number of chemical radicals, for example with C2-C4-alkyl, C3-C4-alkenyl, C3-C4-alkynyl, xe2x80x94Sxe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94Nxe2x80x94COxe2x80x94CH2xe2x80x94Oxe2x80x94, it being possible for each of these radicals to be substituted one or more times by: halogen, hydroxyl, mercapto, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, carboxyl, nitro, cyano, C1-C4-alkoxy, C3-C6-alkenyloxy, C3-C6-alkynyloxy, C1-C4-alkylthio, C1-C4-haloalkoxy, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, C3-C8-alkylcarbonylalkyl, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, phenyl which can be substituted one or more times, eg. one to three times, by halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkylthio.
Or the spacer Q is part of a 5-7-membered heterocyclic or carbocyclic ring to which R6 is fused.
The following definitions apply thereto and hereinafter:
An alkali metal is, for example, lithium, sodium, potassium;
An alkaline earth metal is, for example, calcium, magnesium, barium;
C3-C8-cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl;
C1-C4-haloalkyl can be linear or branched, such as, for example fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl or pentafluoroethyl;
C1-C4-haloalkoxy can be linear or branched, such as, for example, difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2,2-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-1,1,2-trifluoroethoxy, 2-fluoroethoxy or pentafluoroethoxy;
C1-C4-alkyl can be linear or branched, such as, for example, methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl or 2-butyl;
C2-C4-alkenyl can be linear or branched, such as, for example, ethenyl, 1-propen-3-yl, 1-propen-2-yl, 1-propen-1-yl, 2-methyl-1-propenyl, 1-butenyl or 2-butenyl;
C2-C4-alkynyl can be linear or branched, such as, for example, ethynyl, 1-propyn-1-yl, 1-propyn-3-yl, 1-butyn-4-yl or 2-butyn-4-yl;
C1-C4-alkoxy can be linear or branched, such as, for example, methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy;
C3-C6-alkenyloxy can be linear or branched, such as, for example, allyloxy, 2-buten-1-yloxy or 3-buten-2-yloxy;
C1-C4-hydroxyalkyl can be linear or branched, such as, for example, hydroxymethyl, 1-hydroxyether-2-yl,
C3-C6-alkynyloxy can be linear or branched, such as, for example, 2-propyn-1-yloxy, 2-butyn-1-yloxy or 3-butyn-2-yloxy;
C1-C4-alkylthio can be linear or branched, such as, for example, methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio or 1,1-dimethylethylthio;
C1-C4-alkylcarbonyl can be linear or branched, such as, for example, acetyl, ethylcarbonyl or 2-propylcarbonyl;
C1-C4-alkoxycarbonyl can be linear or branched, such as, for example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl or n-butoxycarbonyl;
C3-C8-alkylcarbonylalkyl can be linear or branched, such as, for example, 2-oxo-1-propyl, 3-oxo-1-butyl or 3-oxo-2-butyl
C1-C8-alkyl can be linear or branched, such as, for example, C1-C4-alkyl, pentyl, hexyl, heptyl or octyl;
halogen is, for example fluorine, chlorine, bromine, iodine.
The invention furthermore relates to those compounds from which compounds of the formula I can be liberated (called prodrugs).
Preferred prodrugs are those with which release takes place under conditions like those prevailing in certain compartments of the body, eg. in the stomach, intestine, bloodstream, liver.
The compounds, and the intermediates for preparing them, such as II, III and IV, may have one or more asymmetrically substituted carbon atoms. Such compounds can be in the form of pure enantiomers or pure diastereomers or mixture thereof. An enantiomerically pure compound is preferably used as active substance.
The invention furthermore relates to the use of the abovementioned carboxylic acid derivatives for producing drugs, in particular for producing inhibitors of ETA and ETB receptors. The compounds according to the invention are particularly suitable as mixed antagonists as defined at the outset.
Compounds of the formula IV where Z is sulfur or oxygen can be prepared as described in WO 96/11914, also in enantiomerically pure form. 
Compounds of the formula III are known or can be synthesized, for example, by reducing the corresponding carboxylic acids or esters thereof or by other conventional methods.
Carboxylic acid derivatives of the formula IV [sic] can also be prepared by reacting a compound of the formula IVa with an alcohol or thiol of the formula VII with acid catalysis. 
The indicated radicals have the following meanings:
R1 has the meaning indicated for formula I
R16 and R17, which may be identical or different, hydrogen or alkyl, alkenyl, alkynyl, phenyl, naphthyl, cycloalkyl, in each case unsubstituted or substituted,
R18 hydrogen or alkyl, alkenyl, alkynyl, phenyl, naphthyl, cycloalkyl, in each case unsubstituted or substituted,
R19 hydrogen or alkyl, alkenyl, alkynyl, phenyl, naphthyl, cycloalkyl, in each case unsubstituted or substituted,
and the radicals preferably have the following meanings:
R1 COOR7 
R16 and R17, which may be identical or different, alkyl, phenyl, naphthyl, cycloalkyl, in each case unsubstituted or substituted,
R18 alkyl, phenyl, cycloalkyl, in each case unsubstituted or substituted,
R19 alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, in each case unsubstituted or substituted,
and the following radicals are particularly preferred:
R1 COOCH3 
R16 R4 
R17 R5 
R18 alkyl, unsubstituted or substituted, in particular methyl
R19 R6xe2x80x94Q.
The carboxylic acid derivatives of the formula IV can be prepared by this process by reacting a compound of the formula IVa with an alcohol or thiol of the formula III with acid catalysis 
For this purpose, the compounds IVa and III are mixed without diluent or in a solvent which is inert for this reaction, and catalytic amounts of an acid such as p-toluenesulfonic acid are added. Examples of inert solvents are methylene chloride, benzene or toluene. Also suitable are those inert solvents which form an azeotrope with the alcohol R18OH. In the case of methanol (R18xe2x95x90CH3), examples of these are chloroform or methyl acetate.
The reaction mixture is then stirred at from room temperature to the boiling point of the solvent. The resulting alcohol R18OH is removed by distilling out or reducing the pressure. This method is also suitable for preparing enantiomerically pure IV if the IVa starting material is enantiomerically pure.
Compounds of the formula IVa are known and are described, for example, in WO 96/11914.
The compounds according to the invention in which the substituents have the meanings stated for formula I can be prepared, for example, by reacting the carboxylic acid derivatives of the formula IV in which the substituents have the stated meanings with compounds of the formula V. 
In formula V, R11 is halogen or R12xe2x80x94SO2xe2x80x94 where R12 can be C1-C4-alkyl, C1-C4-haloalkyl or phenyl. In addition, at least one of the ring members X or Y or Z is nitrogen. The reaction preferably takes place in an inert solvent or diluent with the addition of a suitable base, ie. a base which deprotonates the intermediate IV, at a temperature in the range from room temperature to the boiling point of the solvent.
Compounds of type I with R1=COOH can furthermore be obtained directly by deprotonating the intermediate IV where R1 is COOH with two equivalents of a suitable base, and reacting with compounds of the formula V. This reaction also takes place in an inert solvent and at a temperature in the range from room temperature to the boiling point of the solvent.
Examples of such solvents and diluents are aliphatic, alicyclic and aromatic hydrocarbons, each of which may be chlorinated, such as hexane, cyclohexane, petroleum ether, naphtha, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, ethyl chloride and trichloroethylene, ethers such as diisopropyl ether, dibutyl ether, methyl tert-butyl ether, propylene oxide, dioxane and tetrahydrofuran, nitriles such as acetonitrile and propionitrile, amides such as dimethylformamide, dimethylacetamide and N-methylpyrrolidone, sulfoxides and sulfones, for example dimethyl sulfoxide and sulfolane.
Compounds of the formula V are known, and in some cases can be bought or prepared in a conventional way.
The base which can be used is an alkali metal or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, a carbonate such as an alkali metal carbonate, eg. sodium or potassium carbonate, an alkali metal or alkaline earth metal hydroxide such as sodium or potassium hydroxide, an organometallic compound such as butyllithium or an alkali metal amide such as lithium diisopropylamide or lithium amide.
Compounds of the formula I can also be prepared by starting from the corresponding carboxylic acids, ie. compounds of the formula I where R1 is COOH, and converting first them in a conventional way into an activated form, such as a halide, an anhydride or imidazolide, and then reacting the latter with an appropriate hydroxyl compound HOR7. This reaction can be carried out in conventional solvents and often requires the addition of a base, in which case those mentioned above are suitable. These two steps can also be simplified, for example, by allowing the carboxylic acid to act on the hydroxyl compound in the presence of a dehydrating agent such as a carbodiimide.
It is also possible to prepare compounds of the formula I by starting from the salts of the appropriate carboxylic acids, ie. from compounds of the formula I where R1 is COR and R is OM [sic] where M can be an alkali metal cation or the equivalent of an alkaline earth metal cation. These salts can be reacted with many compounds of the formula Rxe2x80x94A where A is a conventional nucleofugic leaving group, for example halogens such as chlorine, bromine, iodine, or aryl- or alkylsulfonyl which is unsubstituted or substituted by halogen, alkyl or haloalkyl, such as toluenesulfonyl and methylsulfonyl, or another equivalent leaving group. Compounds of the formula Rxe2x80x94A with a reactive substituent A are known or can easily be obtained with general expert knowledge. This reaction can be carried out in conventional solvents and is advantageously undertaken with the addition of a base, in which case those mentioned above are suitable.
In some cases it is necessary to use generally known protective group techniques to prepare compounds I according to the invention. If, for example, R6 is to be 4-hydroxyphenyl, it is possible first to protect the hydroxyl group as benzyl ether, which is then cleaved at a suitable stage in the reaction sequence.
Compounds of the formula I where R1 is tetrazole [sic] can be prepared as described in WO 96/11914.
With a view to the biological effect, preferred carboxylic acid derivatives of the formula I, both as pure enantiomers or pure diastereomers or as mixture thereof, are those where the substituents have the following meanings:
R2 hydrogen, hydroxyl, halogen, N(C1-C4-alkyl)2, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkylthio, C1-C4-haloalkyl, C1-C4-haloalkoxy, or CR2 is linked to CR10 as indicated below to give a 5- or 6-membered ring;
X nitrogen or methine;
Y nitrogen or methine;
Z nitrogen or CR10, where R10 is hydrogen or C1-C4-alkyl, or CR10 forms together with CR2 or CR3 a 5- or 6-membered alkylene or alkenylene ring which can be substituted by one or two methyl groups and in which, in each case, one methylene group can be replaced by oxygen or sulfur, such as xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94Oxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CH2Oxe2x80x94, xe2x80x94CH(CH3)xe2x80x94CH(CH3)xe2x80x94Oxe2x80x94, xe2x80x94CH=C(CH3)xe2x80x94Oxe2x80x94, xe2x80x94C(CH3)xe2x95x90C(CH3)xe2x80x94Oxe2x80x94, or xe2x80x94C(CH3)xe2x95x90C(CH3)xe2x80x94S;
At least one of the ring members X, Y or Z is nitrogen.
R3 hydrogen, hydroxyl, halogen, N(C1-C4-alkyl)2, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkylthio, C1-C4-haloalkyl, C1-C4-haloalkoxy, or CR3 is linked to CR10 as indicated above to give a 5- or 6-membered ring;
R4 and R5 (which can be identical or different):
phenyl or naphthyl, which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, mercapto, amino, C1-C4-alkyl, C1-C4-haloalkyl, carboxyl, C1-C4-alkoxy, C1-C4-haloalkoxy, phenoxy, C1-C4-alkylthio, NH(C1-C4-alkyl) or N(C1-C4-alkyl)2 or phenyl which can be substituted one or more times, eg. one to three times, by halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkylthio; or
phenyl or naphthyl, which are connected together in the ortho positions by a direct linkage, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO2xe2x80x94, NHxe2x80x94 or N-alkyl group,
C3-C8-cycloalkyl;
R6 C3-C8-cycloalkyl, it being possible for these radicals in each case to be substituted one or more times by: halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C1-C4-alkoxy, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3-C6-alkenyloxy, C3-C6-alkynyloxy, C1-C4-alkylthio, C1-C4-haloalkoxy, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, NH(C1-C4-alkyl), N(C1-C4-alkyl)2 or phenyl which can be substituted one or more times, eg. one to three times, by halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkylthio;
phenyl or naphthyl, each of which can be substituted by one or more of the following radicals: halogen, R15, nitro, mercapto, carboxyl, cyano, hydroxyl, amino, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3-C6-alkenyloxy, C1-C4-haloalkyl, C3-C6-alkynyloxy, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-alkoxy, C1-C4-haloalkoxy, phenoxy, C1-C4-alkylthio, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, dioxomethylene [sic], dioxoethylene [sic] or phenyl which can be substituted one or more times, eg. one to three times, by halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkylthio;
a five- or six-membered heteroaromatic system containing one to three nitrogen atoms and/or one sulfur or oxygen atom, which can carry one to four halogen atoms and/or one to two of the following radicals: C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-alkylthio, phenyl, phenoxy or phenylcarbonyl, where the phenyl radicals in turn can carry one to five halogen atoms and/or one to three of the following radicals: C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and/or C1-C4-alkylthio;
R15 methyl, ethyl, methoxy or ethoxy which carry one of the following radicals: hydroxyl, carboxyl, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, carboxamide [sic] or CON(C1-C4-alkyl)2;
W sulfur or oxygen;
Q C2-C4-alkyl, C3-C4-alkenyl, C3-C4-alkynyl, xe2x80x94Sxe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94, it being possible for each of these radicals to be substituted one or more times by: halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkylthio, C1-C4-haloalkoxy, C1-C4-alkoxycarbonyl, NH(C1-C4-alkyl), N(C1-C4-alkyl)2 or phenyl which can be substituted one or more times, eg. one to three times, by halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkylthio
or Q forms together with R6 the following ring systems: 2-indanyl, 3-indanyl, 1,2,3,4-tetrahydro-2-naphthyl, 1,2,3,4-tetrahydro-3-naphthyl, it being possible for the phenyl rings in each case to be substituted by: halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C1-C4-alkoxy, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3-C6-alkenyloxy, C3-C6-alkynyloxy, C1-C4-alkylthio, C1-C4-haloalkoxy, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2 or phenyl.
Particularly preferred compounds of the formula I, both as pure enantiomers and pure diastereomers or mixtures thereof, are those where the substituents have the following meanings:
R2 trifluoromethyl, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkylthio, or CR2 is linked to CR10 as indicated below to give a 5- or 6-membered ring;
X nitrogen or methine;
Y nitrogen or methine;
Z nitrogen or CR10 where R10 is hydrogen or C1-C4-alkyl, or CR10 forms together with CR2 or CR3 a 5- or 6-membered alkylene or alkenylene ring which can be substituted by one or two methyl groups and in which in each case a methylene group can be replaced by oxygen or sulfur, such as xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94Oxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CH2Oxe2x80x94, xe2x80x94CH(CH3)xe2x80x94CH(CH3)xe2x80x94Oxe2x80x94, xe2x80x94CH=C(CH3)xe2x80x94Oxe2x80x94, xe2x80x94C(CH3)xe2x95x90C(CH3)xe2x80x94Oxe2x80x94, or xe2x80x94C(CH3)xe2x95x90C(CH3)xe2x80x94S;
At least one of the ring members X, Y or Z is nitrogen
R3 trifluoromethyl, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkylthio, or CR3 is linked to CR10 as indicated above to give a 5- or 6-membered ring;
R4 and R5 (which can be identical or different):
phenyl or naphthyl, which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, mercapto, amino, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, phenoxy, C1-C4-alkylthio, NH(C1-C4-alkyl) or N(C1-C4-alkyl)2 or phenyl which can be substituted one or more times, eg. one to three times, by halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkylthio; or
phenyl or naphthyl, which are connected together in the ortho positions by a direct linkage, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO2xe2x80x94, NHxe2x80x94 or N-alkyl group
C5-C7-cycloalkyl;
R6 C5-C7-cycloalkyl, it being possible for these radicals in each case to be substituted one or more times by: C1-C4-alkoxy,
C1-C4-alkyl, C1-C4-alkylthio, halogen, hydroxyl, carboxyl, cyano, trifluoromethyl, acetyl, or phenyl which can be substituted one or more times, eg. one to three times, by halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkylthio;
phenyl or naphthyl, each of which can be substituted by one or more of the following radicals: halogen, R15, nitro, mercapto, carboxyl, cyano, hydroxyl, amino, C1-C4-alkyl, C1-C4-haloalkyl, acetyl, C1-C4-alkoxycarbonyl, C1-C4-alkoxy, C1-C4-haloalkoxy, phenoxy, C1-C4-alkylthio, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, dioxomethylene [sic], dioxoethylene [sic] or
phenyl which can be substituted one or more times, eg. one to three times, by halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkylthio;
a five- or six-membered heteroaromatic system containing one to three nitrogen atoms and/or one sulfur or oxygen atom, which can carry one to four halogen atoms and/or one to two of the following radicals: C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, trifluoromethoxy, C1-C4-alkylthio, phenyl or phenoxy, it being possible for the phenyl radicals in turn to carry one to five halogen atoms and/or one to three of the following radicals: C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and/or C1-C4-alkylthio;
R15 methoxy or ethoxy which carry one of the following radicals: hydroxyl, carboxyl, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, carboxamide [sic] or CON(C1-C4-alkyl)2;
W sulfur or oxygen;
Q C2-C4-alkyl, C3-C4-alkenyl, C3-C4-alkynyl, xe2x80x94Sxe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94, it being possible for each of these radicals to be substituted one or more times by: halogen, hydroxyl, mercapto, carboxyl, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkylthio, or phenyl which can be substituted one or more times, eg. one to three times, by halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkylthio
or Q forms together with R6 the following ring systems: 2-indanyl, 3-indanyl, 1,2,3,4-tetrahydro-2-naphthyl, 1,2,3,4-tetrahydro-3-naphthyl, it being possible for the phenyl rings in each case to be substituted by: halogen, hydroxyl, mercapto, carboxyl, cyano, C1-C4-alkoxy, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3-C6-alkenyloxy, C3-C6-alkynyloxy, C1-C4-alkylthio, C1-C4-haloalkoxy, C1-C4-alkoxycarbonyl, NH(C1-C4-alkyl), N(C1-C4-alkyl)2 or phenyl.
The compounds of the present invention offer a novel therapeutic potential for the treatment of hypertension, pulmonary hypertension, myocardial infarct, chronic heart failure, angina pectoris, acute/chronic kidney failure, renal insufficiency, cerebral vasospasms, cerebral ischemia, subarachnoid hemorrhages, migraine, asthma, atherosclerosis, endotoxic shock, endotoxin-induced organ failure, intravascular coagulation, restenosis after angioplasty, benign prostate hyperplasia, kidney failure and hypertension caused by ischemia and intoxication, metastasis and growth of mesenchymal tumors, kidney failure induced by contrast agents, pancreatitis, gastrointestinal ulcers.
The compounds according to the invention surprisingly also show in some cases an antagonistic action on the neurokinin receptor.
This is particularly true of compounds of the formula I where R1 is 
The invention furthermore relates to combination products consisting of endothelin receptor antagonists of the formula I and inhibitors of the renin-angiotensin system. Inhibitors of the renin-angiotensin system are renin inhibitors, angiotensin II antagonists and, in particular, angiotensin converting enzyme (ACE) inhibitors.
The invention further relates to combination products of xcex2 blockers and the abovementioned endothelin receptor antagonists, and of mixed ACE/neutral endopeptidase (NEP) inhibitors and the abovementioned endothelin receptor antagonists.
The combination products can be administered in a single pharmaceutical form or else in spatially separate forms. Administration may take place simultaneously or sequentially.
The dosage of the combination may be up to the maximum single dose in each case. However, it is also possible to employ lower doses than in the single therapy in each case.
These combination products are particularly suitable for the treatment and prevention of hypertension and its sequelae, and for the treatment of heart failure.
The good effect of the compounds can be shown in the following tests:
Cloned human ETA or ETB receptor-expressing CHO cells were employed for binding studies.
The ETA or ETB receptor-expressing CHO cells were grown in DMEM NUT MIX F12 medium (Gibco, No. 21331-020) with 10% fetal calf serum (PAA Laboratories GmbH, Linz, No. A15-022), 1 mM glutamine (Gibco No. 25030-024), 100 U/ml penicillin and 100 xcexcg/ml streptomycin (Gibco, Sigma No. P-0781). After 48 hours, the cells were washed with PBS and incubated with 0.05% trypsin-containing PBS at 37xc2x0 C. for 5 minutes. Neutralization with medium was then carried out, and the cells were collected by centrifugation at 300xc3x97g.
For the membrane preparation, the cells were adjusted to a concentration of 108 cells/ml of buffer (50 mM tris.HCL buffer, pH 7.4) and then disintegrated by ultrasound (Branson Sonifier 250, 40-70 seconds/constant/output 20).
For the ETA and ETB receptor binding assays, the membranes were suspended in incubation buffer (50 mM tris-HCl, pH 7,4 with 5 mM MnCl2, 40 xcexcg/ml bacitracin and 0.2% BSA) at a concentration of 50 xcexcg of protein per assay mixture, and incubated with 25 pM 125I-ET1 (ETA receptor assay) or 25 pM 125I-ET3 (ETB receptor assay) in the presence and absence of test substance at 25xc2x0 C. The nonspecific binding was determined with 10xe2x88x927 M ET1. Filtration was carried out after 30 min through GF/B glassfiber filters (Whatman, England) in a Skatron cell collector (Skatron, Lier, Norway) to separate free and bound radio ligands, and the filters were washed with ice-cold tris-HCl buffer, pH 7.4 with 0.2% BSA. The radioactivity collected on the filters was quantified using a
Packard 2200 CA liquid scintillation counter.
Testing of the ET antagonists in vivo:
Male SD rats weighing 250-300 g were anesthetized with amobarbital, artificially ventilated, vagotomized and pithed. The carotid artery and jugular vein were catheterized.
Intravenous administration of 1 xcexcg/kg ET1 to control animals led to a marked rise in blood pressure, which persisted for a lengthy period.
The test animals received i.v. injections of the test compounds (1 ml/kg) 30 min before administration of ET1. To determine the ET-antagonistic properties, the changes in blood pressure in the test animals were compared with those in the control animals.
Oral testing of the mixed ETA and ETB antagonists:
Normotensive male rats (Sprague Dawley, Janvier) weighing 250-350 g are pretreated orally with the test substances. 80 minutes later, the animals are anesthetized with urethane, and the carotid artery (for measuring the blood pressure) and the jugular vein (administration of big endothelin/endothelin 1) are catheterized.
After a stabilization period, big endothelin (20 xcexcg/kg, administration volume 0.5 ml/kg) or ET1 (0.3 xcexcg/kg, administration volume 0.5 ml/kg) is given intravenously. The blood pressure and heartrate are recorded continuously for 30 minutes. The marked and long-lasting changes in blood pressure are calculated as area under the curve (AUC). To determine the antagonistic effect of the test substances, the AUC for the animals treated with the substance is compared with the AUC for the control animals.
The compounds according to the invention can be administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally) in a conventional way. Administration may also take place with vapors or sprays through the nasopharyngeal space.
The dosage depends on the age, condition and weight of the patient and on the mode of administration. As a rule, the daily dose of active substance is about 0.5-50 mg/kg of bodyweight on oral administration and about 0.1-10 mg/kg of bodyweight on parenteral administration.
The novel compounds can be used in conventional solid or liquid pharmaceutical forms, eg. as uncoated or (film-)coated tablets, capsules, powders, granules, suppositories, solutions, ointments, creams or sprays. These are produced in a conventional way. For this purpose, the active substances can be processed with conventional pharmaceutical auxiliaries such as tablet binders, bulking agents, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, release-slowing agents, antioxidants and/or propellant gases (cf. H. Sucker et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1991). The administration forms obtained in this way normally contain from 0.1 to 90% by weight of active substance.